The major objective is to investigate strategies for alleviating photoreceptor degeneration caused by mutations in the RPGR gene. RPGR mutations account for 11 percent of all retinitis pigmentosa (RP) and are associated with a more severe form of the disease. They are, therefore, of great clinical importance. Since RPGR mutations are X-linked recessive, the disease causing alleles are null. Thus a strategy based on replacement gene therapy is likely to be viable and will be investigated. At present, the myriad of RPGR transcript variants coupled with a complete lack of knowledge as to which variant encodes the essential function hampers efforts toward that goal. We will test the hypothesis that a single RPGR variant will be sufficient to reconstitute fully the RPGR function(s) in vivo. After determining the functionally relevant RPGR variant, we will investigate the technical feasibility of gene therapy through somatic gene transfer. We will also test the hypothesis that light exposure may be a necessary trigger for disease progression in RPGR mutations and that limiting light exposure may be a meaningful therapy. Finally, we will seek further insight into RPGR function by examining the physiological significance of an RPGR interacting protein in photoreceptor cells. The long-term goal of the application is to help lay down the groundwork for phenotype rescue, genetically or otherwise, of RPGR mutations by promoting a greater understanding of its function in photoreceptor cells.